The present invention relates to processes for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol prepared by the present invention may be utilized in the synthesis of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
which is a known intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol in relatively high yield and enantiomeric purity.
It will be appreciated that (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol via a very simple, short and highly efficient synthesis.
The novel process of this invention involves the synthesis of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula: 
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
The present invention is directed to processes for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol of the formula: 
An embodiment of the general process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol is as follows: 
In accordance with this embodiment of the present invention, the treatment of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one with a rhodium or a ruthenium catalyst and a ligand in the presence of an alcohol provides (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol in higher yields, in greater entantiomeric purity and in a more efficient route than the processes disclosed in the art.
In another embodiment, the present invention is directed to a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol which comprises the treatment of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one with a rhodium a ruthenium catalyst and a ligand in the presence of an alcohol to give (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol.
A specific embodiment of the present invention concerns a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol of the formula: 
which comprises:
treating 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
with a rhodium or a ruthenium catalyst and a ligand in the presence of an alcohol;
to give (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol of the formula: 
In the present invention, it is preferred that the rhodium catalyst is selected from bis((pentamethylcyclopentadienyl)rhodium chloride) (i.e. ((pentamethylcyclopentadienyl)RhCl2)2) and bis((cyclopentadienyl)rhodium chloride) (i.e. ((cyclopentadienyl)RhCl2)2). The preferred rhodium catalyst is bis((pentamethylcyclopentadienyl)rhodium chloride). The rhodium catalyst is preferably present at a concentration of about 0.1-1 mol % and more preferably about 0.5 mol %.
In the present invention, it is preferred that the ruthenium catalyst is selected from bis((4-isopropyl-toluenyl)ruthenium chloride) and bis((cyclopentadienyl)ruthenium chloride). The preferred ruthenium catalyst is bis((4-isopropyl-toluenyl)ruthenium chloride) [i.e. bis((para-cymenyl)ruthenium chloride))]. The ruthenium catalyst is preferably present at a concentration of about 0.1-1 mol % and more preferably about 0.3 mol %.
To minimize expense, the use of a ruthenium catalyst is preferred.
In the present invention, it is preferred that the ligand is selected from (R,R)-cyclohexane diamine (R,R)CHXD, pseudoephedrine, nor-pseudoephedrine, ephedrine, nor-ephedrine and (S,R)-cis-1-amino-2-hydroxy-indane. In the present invention, it is more preferred that the ligand is (S,R)-cis-1-amino-2-hydroxy-indane. The ligand is preferably present at a concentration of about 0.1-1 mol % and more preferably about 0.5 mol %.
For convenience, the rhodium or ruthenium catalyst and the ligand may be contacted together in situ. In the present invention the rhodium or ruthenium catalyst and the ligand optionally may be contacted together to form a catalyst-ligand complex prior to reaction with (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol.
In an alternate embodiment, the present invention is directed to a compound which is: 
wherein Cp* is pentamethylcyclopentadienyl.
In an alternate embodiment, the present invention is directed to a compound which is: 
wherein Cym* is p-cymene (4-isopropyl-toluene).
In the present invention, it is preferred that the alcohol is selected from methanol, ethanol, isopropanol, isobutanol or n-butanol. The most preferred alcohol is isopropanol. Although other solvents may also be present, for convenience it is preferred that the alcohol is employed as a solvent for the conducting the reaction.
In the present invention a base is optionally present with the alcohol. The base may be an inorganic base such as a base selected from potassium or sodium hydroxide, potassium or sodium carbonate, potassium or sodium bicarbonate potassium or sodium alkoxides, and the like. The alkoxides can be derived from lower (C1-C5) or higher ( greater than C6) primary, secondary or tertiary alcohols. A preferred base is sodium hydroxide.
The (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
In an alternate embodiment, the present invention is directed to a process for purification or enhancing the enantiomeric purity of (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol which comprises:
contacting (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol with 1,4-diazabicyclo[2.2.2]octane in an organic solvent to form bis-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol)1,4-diazabicyclo[2.2.2]octane;
recovering the bis-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol)1,4-diazabicyclo[2.2.2]octane;
and optionally dissociating the 1,4-diazabicyclo[2.2.2]octane from the bis-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol)1,4-diazabicyclo[2.2.2]octane to give (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol.
In this process, it is preferred that the organic solvent is an alkane, it is more preferred that the organic solvent is selected from: hexane and heptane and it is even more preferred that the organic solvent is heptane.
The diazabicyclo[2.2.2]octane is preferably present at a ratio of 0.5 equivalents of diazabicyclo[2.2.2]octane to 1.0 equivalents of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol.
The diazabicyclo[2.2.2]octane is preferably present at a concentration of about 0.05-1 mol % and more preferably about 0.5 mol %.
Optionally, the mixture is seeded with bis-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol)1,4-diazabicyclo[2.2.2]octane after contacting (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol with 1,4-diazabicyclo[2.2.2]octane in the organic solvent. The temperature in the formation of bis-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol)1,4-diazabicyclo[2.2.2]octane is preferably about 50xc2x0 C. to about xe2x88x9240xc2x0 C., more preferably about 40xc2x0 C. to about xe2x88x9220xc2x0 C., and even more preferably about 0xc2x0 C. to about xe2x88x9220xc2x0 C.
It will be appreciated by those skilled in the art that this alternate embodiment may be repeated in an itterative manner to further enhance the enantiomeric purity of (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol with each subsequent cycle.
In an aspect of this alternate embodiment, the present invention is directed to a compound which is: 
Another aspect of this alternate embodiment is directed to (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol which is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, preferably greater than 95%, more preferably greater than 98%, particularly greater than 99% and especially greater than 99.5% (enantiomeric excess).
The starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.